Microparticles containing bupropion

ABSTRACT

This disclosure relates to microparticles containing bupropion, e.g., microparticles having a particle diameter of about 50 μm to about 100 μm. These microparticles may be included in pharmaceutical compositions and/or dosage forms for treatment of various disease, such as depression.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Nos.63/357,355, filed Jun. 30, 2022; 63/370,572, filed Aug. 5, 2022; and63/370,778, filed Aug. 8, 2022, all of which are incorporated byreference herein in their entireties.

BACKGROUND

Bupropion is FDA approved for the treatment of depression and smokingcessation.

SUMMARY

This disclosure relates to microparticles containing bupropion. It hasbeen found that the particle size of a microparticle containingbupropion can affect the dissolution profile of bupropion in themicroparticle. This may also affect the pharmacokinetics of bupropion.

Some embodiments include a microparticle comprising bupropionhydrochloride, wherein the microparticle has a particle diameter ofabout 50 μm to about 100 μm; the particle diameter may be determined bylaser diffraction or other suitable techniques.

Some embodiments include a dosage form comprising microparticlescontaining bupropion, wherein at least 80% of the microparticles have aparticle diameter of about 1 μm to about 300 μm as determined by laserdiffraction.

Some embodiments include a pharmaceutical composition comprisingmicroparticles containing bupropion, wherein at least 80% of themicroparticles have a particle diameter of about 1 μm to about 300 μm;the particle diameter may be determined by laser diffraction or othersuitable techniques.

DETAILED DESCRIPTION

A microparticle containing bupropion may include, or be prepared from,any suitable form of bupropion, such as a salt form, e.g., bupropionhydrochloride, the free base form, hydrates, solvates, polymorphs, othersolid forms, etc. In some embodiments, the microparticle, or a dosageform or a pharmaceutical composition containing the microparticle, isfree of any other active pharmaceutical agents. In some embodiments, themicroparticle may be present in a dosage form that also contains adextromethorphan in any suitable form, such as a salt form, the freebase form, hydrates, solvates, polymorphs, other solid forms, etc.

The microparticles may contain any suitable amount of the bupropion. Forexample, the bupropion, e.g., bupropion hydrochloride may comprise about1-20%, about 20-40%, about 10-20%, about 15-20%, about 20-25%, about25-30%, about 30-35%, about 35-40%, about 40-60%, about 60-80%, about80-100%, about 20-30%, about 30-33%, or about 31-32% of the weight ofthe microparticles.

When prepared in certain ways, microparticles may be present in adistribution of size. This distribution of size may be described in avariety of ways, but one convenient description is to identify the10^(th) percentile of microparticle diameter, the median microparticlediameter, and the 90^(th) percentile of microparticle diameter.

The 10^(th) percentile of microparticle diameter is the size where 10%of the microparticles are of that diameter or smaller. In someembodiments, the 10^(th) percentile of microparticle diameter is about1-30 μm, about 1-3 μm, about 3-5 μm, about 5-10 μm, about 10-15 μm,about 15-20 μm, about 20-25 μm, or about 25-30 μm; the particle diametermay be determined by laser diffraction or other suitable techniques.

The median microparticle diameter is the diameter where the number ofparticles that are smaller than the median microparticle diameter isequal to the number of particles that are larger than the medianmicroparticle diameter. In some embodiments, the microparticles have amedian particle diameter of about 50-100 μm, about 50-55 μm, about 55-60μm, about 60-65 μm, about 65-70 μm, about 70-75 μm, about 75-80 μm,about 80-85 μm, about 85-90 μm, about 80-90 μm, about 95-100 μm, about50-60 μm, about 60-70 μm, about 70-80 μm, about 80-90 μm, about 90-100μm, about 50-75 μm, or about 75-100 μm; the particle diameter may bedetermined by laser diffraction or other suitable techniques.

The 90^(th) percentile of microparticle diameter is the size where 90%of the microparticles are of that diameter or smaller. In someembodiments, 90^(th) percentile of microparticle diameter is about200-300 μm, about 200-210 μm, about 210-220 μm, about 220-230 μm, about230-240 μm, about 240-250 μm, about 250-260 μm, about 260-270 μm, about270-280 μm, about 280-290 urn, about 290-300 μm, about 200-240 μm, about240-270 μm, or about 270-300 μm; the particle diameter may be determinedby laser diffraction or other suitable techniques.

The particle size distribution may also be characterized as a range ofparticle sizes, such as particle diameters, within which at least about80% (e.g., at least particles from the 10^(th) to the percentile) of themicroparticles would fall. In some embodiments, at least about 80% ofthe microparticles have a particle diameter of about 1-300 μm, about2-260 μm, or about 20-230 μm; the particle diameter may be determined bylaser diffraction or other suitable techniques.

The particle size distribution may be further characterized by the ratiobetween the particle size of the 90^(th) percentile of microparticlediameter and the median microparticle diameter, the ratio between theparticle size of the median and the 10^(th) percentile of microparticlediameter, and the ratio between the 90^(th) percentile of microparticlediameter and the 10^(th) percentile of microparticle diameter.

In some embodiments, the ratio between the 90^(th) percentile ofmicroparticle diameter and the median microparticle diameter is about2-10 (e.g., if the 90^(th) percentile has a diameter that is twice thatof the median, the ratio is 2), about 2-3, about 3-4, about 4-5, about5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4, about 4-6,about 6-8, about 8-10, about 2-6, or about 6-10.

In some embodiments, the ratio between the median microparticle diameterand the 10^(th) percentile of microparticle diameter is about 2-50,about 2-6, about 6-10, about 10-15, about 15-about 20-25, about 25-30,about 30-35, about 35-40, about 40-45, about 45-50, about 2-10, about10-20, about 20-30, about 30-40, about 40-50, about 2-20, or about20-50.

In some embodiments, the ratio between the 90^(th) percentile ofmicroparticle diameter and the 10^(th) percentile of microparticlediameter is about 5-200, about 5-20, about 20-40, about 40-60, about60-80, about 80-100, about 100-120, about 120-140, about 140-160, about160-180, about 180-200, about 5-50, about 50-120, or about 120-200.

The microparticles may be formulated into a pharmaceutical compositionor a dosage form. In some embodiments, the microparticles,pharmaceutical composition, or dosage form may comprise a stabilizer,such as cysteine. The pharmaceutical composition may include anysuitable amount of stabilizer, such as about 1-30 mg, about 30-100 mg,about 30-40 mg, about mg, about 50-60 mg, about 60-70 mg, about 70-80mg, about 80-90 mg, about 90-100 mg, or about 65-70 mg of thestabilizer.

The microparticles, pharmaceutical composition, or dosage form mayfurther comprise a sustained release or controlled release polymer, suchas a crosslinked or uncross linked acrylate polymer or copolymer (e.g.,a carbomer copolymer Type A such as Carbopol 971P), a cellulosederivative, such as methylcellulose, etc. In some embodiments, thecontrolled release polymer is about 1-40%, about 1-5%, about 5-10%,about 10-15%, about 15-20%, about 20-30%, about 30-40%, about 11-13%, orabout 12% of the weight of the pharmaceutical composition. In someembodiments, the controlled release polymer is about 0.1-20%, about0.1-2%, about 2-4%, about 4-6%, about 6-8%, about 8-10%, about 10-15%,about 15-20%, or about 7% of the weight of the dosage form.

The microparticles, pharmaceutical composition, or dosage form mayfurther comprise a filler such as microcrystalline cellulose. In someembodiments, the filler may be about 20-60%, about 20-30%, about 30-40%,about 40-50%, or about 50-60% of the weight of the pharmaceuticalcomposition or the dosage form.

The microparticles, pharmaceutical composition, or dosage form mayfurther comprise a lubricant such as magnesium stearate. In someembodiments, the lubricant is about 0.1-10%, about 0.1-2%, about 2-4%,about 4-6%, about 6-8%, or about 8-10% of the weight of thepharmaceutical composition or the dosage form.

The dosage form may be formulated for any suitable route ofadministration, such as oral administration.

Dosage forms, such as solid dosage forms, e.g., capsules, tablets, orpills, for oral administration may also contain one or more of thefollowing: a binder such as gum tragacanth, acacia, corn starch, orgelatin; an excipient, such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid, and the like; asweetening agent such as sucrose, lactose, or saccharin; or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier. Various other materialsmay be present as a coating, for example, tablets, pills, or capsulesmay be coated with shellac, sugar, or both. It may be desirable formaterial in a dosage form or pharmaceutical composition to bepharmaceutically pure and nontoxic in the amounts employed.

The dosage form may further contain a second active pharmaceuticalingredient, such as dextromethorphan, e.g., dextromethorphanhydrobromide. In some embodiments, the dosage form may contain bupropionand dextromethorphan, and no other active pharmaceutical ingredients. Insome embodiments, the bupropion and the dextromethorphan are in twodifferent layers or phases of the dosage form, e.g., each layer containsonly bupropion or dextromethorphan and none of the other.

In some embodiments, the dosage form contains cysteine, Carbopol 971P,microcrystalline cellulose, silicon dioxide, and magnesium. In someembodiments, the dosage form contains a first layer comprising bupropionand cysteine, and a second layer comprising dextromethorphan,microcrystalline cellulose, croscarmellose sodium, and magnesiumstearate.

An example of the composition of microparticles containing bupropion isshown below.

Composition 1

Ingredient Amount (mg) Bupropion  90-120 Cysteine  1-100 Carbopol 971P20-60 Microcrystalline Cellulose 200-300

Microparticles, such as microparticles shown above, may be formed into alayer in a tablet or dosage form, e.g., by pressing. They could also beenclosed within a capsule.

In some embodiments, a dosage form may contain microparticles containingbupropion and a second therapeutically active agent, such asdextromethorphan. In some embodiments, such a dosage form contains noother therapeutically active agent than bupropion and dextromethorphan.

In dosage forms that include dextromethorphan, the dextromethorphan maybe incorporated into composition 2.

Composition 2

Ingredient Amount (mg) Dextromethorphan 30-60 Microcrystalline Cellulose100-150 Croscarmellose sodium  1-20 Magnesium Stearate  1-10

Composition 1 and Composition 2 may be, e.g., in two separate layers ina tablet, may be two separate powders contained in a capsule, etc. Othertypes of dosage forms may also be formed from Composition 1 andComposition 2.

Microparticles described herein may be prepared, for example, byscreening bupropion, cysteine, Carbopol 971, and MicrocrystallineCellulose from Composition 1 (e.g., through 20 mesh), mixing, spraygranulating, drying, and milling the dried blend. The resulting particlesize distribution can be determined by laser diffraction.

The microparticles, pharmaceutical compositions, or dosage forms,described herein may be useful in treating neurological or psychiatricconditions, such as depression, including major depressive disorder ortreatment-resistant major depressive disorder, agitation, such asagitation associated with Alzheimer's disease, addiction, such asnicotine addiction, etc.

The subject combination may be used for adjunctive treatment of majordepressive disorder or depression.

In addition to major depressive disorder, the subject combination may beused to treat other diseases in conditions in the patient populations orcircumstances described herein. For example, the subject combination maybe used to treat pain or a neurological disorder. Examples ofneurological disorders that may be treated with the subject combinationinclude, but are not limited to: affective disorders, psychiatricdisorders, cerebral function disorders, movement disorders, dementias,motor neuron diseases, neurodegenerative diseases, seizure disorders,and headaches.

Affective disorders that may be treated by the subject combinationinclude, but are not limited to, depression, major depression, treatmentresistant depression, treatment resistant bipolar depression, bipolardisorders including cyclothymia, seasonal affective disorder, mooddisorders, chronic depression (dysthymia), psychotic depression,postpartum depression, premenstrual dysphoric disorder (PMDD),situational depression, atypical depression, mania, anxiety disorders,attention deficit disorder (ADD), attention deficit disorder withhyperactivity (ADDH), and attention deficit/hyperactivity disorder(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder,bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms mayinclude psychological changes such as changes in mood, feelings ofintense sadness, despair, mental slowing, loss of concentration,pessimistic worry, agitation, anxiety, irritability, guilt, anger,feelings of worthlessness, reckless behavior, suicidal thoughts, orattempts, and/or self-deprecation. Physical symptoms of depression mayinclude insomnia, anorexia, appetite loss, weight loss, weight gain,decreased energy and libido, fatigue, restlessness, aches, pains,headaches, cramps, digestive issues, and/or abnormal hormonal circadianrhythms.

Psychiatric disorders that may be treated by the subject combination,include, but are not limited to, anxiety disorders, including but notlimited to, phobias, generalized anxiety disorder, social anxietydisorder, panic disorder, agoraphobia, obsessive-compulsive disorder,and post-traumatic stress disorder (PTSD); mania, manic depressiveillness, hypomania, unipolar depression, depression, stress disorders,somatoform disorders, personality disorders, psychosis, schizophrenia,delusional disorder, schizoaffective disorder, schizotypy, aggression,aggression in Alzheimer's disease, agitation, and agitation inAlzheimer's disease. Alzheimer's disease may also be referred to asdementia of the Alzheimer's type. Other neurobehavioral symptoms ofAlzheimer's disease that may be treated include disinhibition andapathy.

Agitation in Alzheimer's disease occurs as the disease progresses.Agitation may present itself as inappropriate verbal, emotional, and/orphysical behaviors. Inappropriate behaviors may include, but are notlimited to, incoherent babbling, inappropriate emotional response,demands for attention, threats, irritability, frustration, screaming,repetitive questions, mood swings, cursing, abusive language, physicaloutbursts, emotional distress, restlessness, shredding, sleepingdisturbances, delusions, hallucinations, pacing, wandering, searching,rummaging, repetitive body motions, hoarding, shadowing, hitting,scratching, biting, combativeness, hyperactivity, and/or kicking.

Alzheimer's disease (AD) is a progressive neurodegenerative disordercharacterized by cognitive decline, and behavioral and psychologicalsymptoms including agitation. AD is the most common form of dementia andafflicts an estimated 6 million individuals in the United States, anumber that is anticipated to increase to approximately 14 million by2050. Agitation is reported in up to 70% of patients with AD and ischaracterized by emotional distress, aggressive behaviors, disruptiveirritability, and disinhibition. Managing agitation is a priority in AD.Agitation in patients with AD has been associated with increasedcaregiver burden, decreased functioning, accelerated cognitive decline,earlier nursing home placement, and increased mortality. There arecurrently no therapies approved by the FDA for the treatment ofagitation in patients with AD.

Neurobehavioral symptoms have been known to appear during dementia andmay be treated by the combination. Caregivers or families may feel moreoverwhelmed by patients' behavioral/psychological symptoms than by theircognitive impairment. Common forms of the syndrome are Alzheimer'sdisease, vascular dementia, dementia with Lewy bodies (abnormalaggregates of protein that develop inside nerve cells), and a group ofdiseases that contribute to frontotemporal dementia (degeneration of thefrontal lobe of the brain). The symptoms that dementia patients have aresimilar to those of psychiatric disorders, but some are slightlydifferent from each other. Neurobehavioral symptoms associated withdementia include depression, apathy, agitation, disinhibition,hallucinations, delusions, psychosis, impulsiveness, aggressiveness,compulsion, excessive sex drive, and personality disorders.Neurobehavioral symptoms such as disinhibition may also be found inother conditions such as traumatic brain injury.

Agitation in patients with Alzheimer's disease may be assessed using theCohen Mansfield Agitation Inventory or CMAI. The CMAI assesses variousbehaviors including, hitting (including self), Kicking, grabbing ontopeople, pushing, throwing things, biting, scratching, spitting, hurtingself or others, tearing things or destroying property, making physicalsexual advances, pacing, aimless wandering, inappropriate dress ordisrobing, trying to get to a different place, intentional falling,eating/drinking inappropriate substances, handling thingsinappropriately, hiding things, hoarding things, performing repetitivemannerisms, general restlessness, screaming, making verbal sexualadvances, cursing or verbal aggression, repetitive sentences orquestions, strange noises (weird laughter or crying), complaining,negativism, constant unwarranted request for attention or help.

Schizophrenia may treated by the combination including positive symptomsand/or negative symptoms of schizophrenia, or residual symptoms ofschizophrenia. Other conditions that may treated include intermittentexplosive disorder.

Cerebral function disorders that may be treated by the subjectcombination include, but are not limited to, disorders involvingintellectual deficits such as senile dementia, Alzheimer's typedementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbancesof consciousness, coma, lowering of attention, speech disorders, voicespasms, Parkinson's disease, Lennox-Gastaut syndrome, autism,hyperkinetic syndrome, and schizophrenia. Cerebral function disordersalso include disorders caused by cerebrovascular diseases including, butnot limited to, stroke, cerebral infarction, cerebral bleeding, cerebralarteriosclerosis, cerebral venous thrombosis, head injuries, and thelike where symptoms include disturbance of consciousness, seniledementia, coma, lowering of attention, and speech disorders.

Substance addiction abuse that may be treated by the subject combinationincludes, but is not limited to, drug dependence, addiction to cocaine,psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol,opioids, anxiolytic and hypnotic drugs, cannabis (marijuana),amphetamines, hallucinogens, phencyclidine, volatile solvents, andvolatile nitrites. Nicotine addiction includes nicotine addiction of allknown forms, such as smoking cigarettes, cigars and/or pipes,e-cigarettes or vaping, and addiction to chewing tobacco.

Movement disorders that may be treated by the subject combinationinclude, but are not limited to, akathisia, akinesia, associatedmovements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia,cerebral palsy, chorea, Huntington's disease, Huntington's diseasechorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardivedyskinesia, dystonia, blepharospasm, spasmodic torticollis,dopamine-responsive dystonia, Parkinson's disease, restless legssyndrome (RLS), tremor, essential tremor, and Tourette's syndrome, andWilson's disease.

Dementias that may be treated by the subject combination include, butare not limited to, Alzheimer's disease, Parkinson's disease, vasculardementia, dementia with Lewy bodies, mixed dementia, fronto-temporaldementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by the subject combinationinclude, but are not limited to, amyotrophic lateral sclerosis (ALS),progressive bulbar palsy, primary lateral sclerosis (PLS), progressivemuscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy(SMA), spinal motor atrophies, Tay-Sach's disease, Sandoff disease, andhereditary spastic paraplegia.

Neurodegenerative diseases that may be treated the subject combinationinclude, but are not limited to, Alzheimer's disease, prion-relateddiseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinalmuscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiplesclerosis (MS), multiple system atrophy, Shy-Drager syndrome,corticobasal degeneration, progressive supranuclear palsy, Wilson'sdisease, Menkes disease, adrenoleukodystrophy, cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT),familial spastic paraparesis, neurofibromatosis, olivopontine cerebellaratrophy or degeneration, striatonigral degeneration, Guillain-Barrésyndrome, and spastic paraplegia.

Seizure disorders that may be treated by the subject combinationinclude, but are not limited to, epileptic seizures, nonepilepticseizures, epilepsy, febrile seizures; partial seizures including, butnot limited to, simple partial seizures, Jacksonian seizures, complexpartial seizures, and epilepsia partialis continua; generalized seizuresincluding, but not limited to, generalized tonic-clonic seizures,absence seizures, atonic seizures, myoclonic seizures, juvenilemyoclonic seizures, and infantile spasms; and status epilepticus.

Types of headaches that may be treated by the subject combinationinclude, but are not limited to, migraine, tension, and clusterheadaches.

Other neurological disorders that may be treated by the subjectcombination include, but are not limited to, Rett Syndrome, autism,tinnitus, disturbances of consciousness disorders, sexual dysfunction,intractable coughing, narcolepsy, cataplexy; voice disorders due touncontrolled laryngeal muscle spasms, including, but not limited to,abductor spasmodic dysphonia, adductor spasmodic dysphonia, musculartension dysphonia, and vocal tremor; diabetic neuropathy,chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity;incontinence including, but not limited to, stress urinary incontinence,urge urinary incontinence, and fecal incontinence; and erectiledysfunction.

In some embodiments, the subject combination may be used to treat pain,joint pain, pain associated with sickle cell disease, pseudobulbaraffect, depression (including treatment resistant depression), disordersrelated to memory and cognition, schizophrenia, Parkinson's disease,amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough(including chronic cough), etc.

In some embodiments, the subject combination may be administered orallyto relieve musculoskeletal pain including low back pain, and painassociated with rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid)arthropathies, non-articular rheumatism, peri-articular disorders, axialspondyloarthritis including ankylosing spondylitis, Paget's disease,fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip,vertebral crush fractures, osteoporosis, etc.

In some embodiments, the subject combination may be administered torelieve inflammatory pain including musculoskeletal pain, arthritispain, and complex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, the subject combination is used to treat chronicmusculoskeletal pain.

In some embodiments, the subject composition may be administered torelieve complex regional pain syndrome, such as complex regional painsyndrome type I (CRPS-I), complex regional pain syndrome type II(CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type ofinflammatory pain. CRPS can also have a neuropathic component. Complexregional pain syndrome is a debilitating pain syndrome. It ischaracterized by severe pain in a limb that can be accompanied by edema,and autonomic, motor, and sensory changes.

In some embodiments, the subject composition may be administered orallyto relieve neuropathic pain.

Examples of neuropathic pain include pain due to diabetic peripheralneuropathy or diabetic peripheral neuropathic pain, post-herpeticneuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain,central pain, pain due to multiple sclerosis, etc. Other causes ofneuropathic pain include cancer-related pain, lumbar nerve rootcompression, spinal cord injury, post-stroke pain, central multiplesclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapyassociated neuropathy, etc.

In some embodiments, the subject composition may be administered torelieve fibromyalgia.

The term “treating” or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

A subject combination may be used to treat any disease or conditionidentified as treatable by the combination of bupropion anddextromethorphan in any of the following U.S. Pat. Nos. 8,569,328,9,168,234, 9,189,905 9,205,083, 9,238,032, 9,278,095, 9,314,462,9,370,513, 9,375,429, 9,408,815, 9,421,176, 9,457,023, 9,457,025,9,474,731, 9,486,450, 9,700,528, 9,700,553, 9,707,191, 9,763,932,9,861,595, 9,867,819, 9,968,568, 10,058,518, 10,064,857, 10,092,560,10,092,561, 10,105,327, 10,105,361, 10,251,879, 10,463,634, 10,512,643,10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066, 10,786,469,10,799,497, 10,806,710, 10,864,209, 10,874,663, 10,874,664, 10,874,665,10,881,657, 10,894,046, 10,894,047, 10,898,453, all of which areincorporated by reference herein in their entireties for theirdisclosure of diseases that may be treated by a combination of bupropionand dextromethorphan, including specific embodiments and combinationsdescribed therein.

The following documents are incorporated by reference herein in theirentireties: MEDICATION GUIDE for AUVELITY™(www.axsome.com/auvelity-medication-guide.pdf), and HIGHLIGHTS OFPRESCRIBING INFORMATION for AUVELITY™(www.axsome.com/auvelity-prescribing-information.pdf).

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

Use of the term “comprising” or “comprises” herein also contemplatesthat use of “consisting essentially of,” “consists essentially of,”“consisting of,” or “consists of” in its place.

Affirmative recitation of an element anywhere herein should beunderstood to contemplate both including and excluding that element.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from a group, forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. A dosage form comprisingmicroparticles containing about 105 mg bupropion hydrochloride and about40 mg to about 70 mg of a cysteine, wherein at least about 80% of themicroparticles have a particle diameter of about 1 μm to about 300 μm.5. The dosage form of claim 4, wherein the particle diameter isdetermined by laser diffraction.
 6. The dosage form of claim 4, whereinthe median microparticle diameter is about μm to about 100 μm asdetermined by laser diffraction.
 7. A dosage form comprisingmicroparticles containing bupropion hydrochloride, wherein at leastabout 80% of the microparticles have a particle diameter of about 1 μmto about 300 μm, and wherein the 10^(th) percentile of microparticlediameter is about 1 μm to about 30 μm as determined by laserdiffraction.
 8. The dosage form of claim 7, wherein the 90^(th)percentile of microparticle diameter is about 200 μm to about 300 μm asdetermined by laser diffraction.
 9. The dosage form of claim 7, whereinthe 90^(th) percentile of microparticle diameter is about 2 times toabout 10 times the median microparticle diameter as determined by laserdiffraction.
 10. (canceled)
 11. (canceled)
 12. The dosage form of claim7, further comprising microcrystalline cellulose.
 13. (canceled) 14.(canceled)
 15. The dosage form of claim 7, wherein the microparticlescontaining bupropion have a median particle diameter of about 50 μm toabout 100 μm as determined by laser diffraction.
 16. A pharmaceuticalcomposition comprising microparticles containing bupropion, wherein atleast 80% of the microparticles have a particle diameter of about 1 μmto about 300 μm, and wherein microparticles in the 10^(th) percentilebased upon particle diameter have a diameter of about 1 μm to about 30μm as determined by laser diffraction.
 17. The pharmaceuticalcomposition of claim 16, wherein microparticles in the 90^(th)percentile based upon particle diameter have a diameter of about 200 μmto about 300 μm as determined by laser diffraction.
 18. Thepharmaceutical composition of claim 16, wherein the 90^(th) percentileof microparticle diameter is about 2 times to about 10 times the medianmicroparticle diameter as determined by laser diffraction. 19.(canceled)
 20. (canceled)
 21. The pharmaceutical composition of claim16, further comprising a sustained release or controlled releasepolymer.
 22. The pharmaceutical composition of claim 16, furthercomprising magnesium stearate.